Mathematical modeling and computational biology are increasingly appreciated for their contribution to the analysis and understanding of practical biological and medical problems. With regard to HIV infection, for example, such approaches have been instrumental in generating testable hypotheses regarding viral persistence and evolution, in providing insights into dynamics and pathogenesis, and in the analysis of nucleotide sequence data to investigate viral escape from the selective pressure of immune responses and antiretroviral treatment. Investigation of HIV pathogenesis and treatment requires both excellent clinical and laboratory investigators and is enhanced by the cross-disciplinary input of quantitative biologists. This proposal aims to establish at UCSD expertise in modeling and theoretical biology to augment the existing translational research programs. The projects in this proposal encompass a number of interrelated subjects that fall into two principal fields: 1) HIV Drug Resistance: a) Evolution of drug resistance in patients receiving combination antiretroviral therapy; b) Analysis of genetic variants conferring differences in susceptibility to protease inhibitors in recently HIV infected individuals; c) Viral fitness and transmission of drug resistant strains of HIV; d) Modeling recombination in the evolution of drug resistant HIV. 2) HIV Replication in Compartments: a) HIV evolution in the central nervous system; b) HIV evolution and dynamics in the genital tract; c) Models for the evolution of HIV in lymphoid tissue; d) Persistence of HIV in resting CD4 lymphocytes.